Cinnoline derivatives as human neutrophil elastase inhibitors

Maria Paola Giovannoni, Igor A. Schepetkin, Letizia Crocetti, Giovanna Ciciani, Agostino Cilibrizzi, Gabriella Guerrini, Andrey Ivanovich Khlebnikov, Mark T. Quinn, Claudia Vergelli

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared to N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value = 56 nM) and chemical stability (t1/2 = 114 min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1H)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195.

Original languageEnglish
Pages (from-to)628-639
Number of pages12
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume31
Issue number4
DOIs
Publication statusPublished - 3 Jul 2016
Externally publishedYes

Fingerprint

Secretory Proteinase Inhibitory Proteins
Leukocyte Elastase
Structure-Activity Relationship
cinnoline
Human Activities
Hydroxyl Radical
Inhibitory Concentration 50
Esters
Binding Sites

Keywords

  • Cinnoline
  • human neutrophil elastase
  • inhibitory activity

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Giovannoni, M. P., Schepetkin, I. A., Crocetti, L., Ciciani, G., Cilibrizzi, A., Guerrini, G., ... Vergelli, C. (2016). Cinnoline derivatives as human neutrophil elastase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(4), 628-639. https://doi.org/10.3109/14756366.2015.1057718

Cinnoline derivatives as human neutrophil elastase inhibitors. / Giovannoni, Maria Paola; Schepetkin, Igor A.; Crocetti, Letizia; Ciciani, Giovanna; Cilibrizzi, Agostino; Guerrini, Gabriella; Khlebnikov, Andrey Ivanovich; Quinn, Mark T.; Vergelli, Claudia.

In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 31, No. 4, 03.07.2016, p. 628-639.

Research output: Contribution to journalArticle

Giovannoni, MP, Schepetkin, IA, Crocetti, L, Ciciani, G, Cilibrizzi, A, Guerrini, G, Khlebnikov, AI, Quinn, MT & Vergelli, C 2016, 'Cinnoline derivatives as human neutrophil elastase inhibitors', Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 31, no. 4, pp. 628-639. https://doi.org/10.3109/14756366.2015.1057718
Giovannoni, Maria Paola ; Schepetkin, Igor A. ; Crocetti, Letizia ; Ciciani, Giovanna ; Cilibrizzi, Agostino ; Guerrini, Gabriella ; Khlebnikov, Andrey Ivanovich ; Quinn, Mark T. ; Vergelli, Claudia. / Cinnoline derivatives as human neutrophil elastase inhibitors. In: Journal of Enzyme Inhibition and Medicinal Chemistry. 2016 ; Vol. 31, No. 4. pp. 628-639.
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